Inhibition of the enkephalin-metabolizing enzymes by the first systemically active mixed inhibitor prodrug RB 101 induces potent analgesic responses in mice and rats.

Abstract

N-([(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxopropyl)-L-phenylalanine benzyl ester (RB101) is the first systemically active prodrug generating through a biologically dependent cleavage of the disulfide bond the potent (S)2-amino-1-mercapto-4-methylthio butane (aminopeptidase N) (IC50 = 11 nM) and N-[(R,S)-2-mercapto-methyl-1-oxo-3-phenylpropyl]-L-phenylalanine (neutral endopeptidase) (IC50 = 2 nM) inhibitors (aminopeptidase N). RB101 easily crosses the blood-brain barrier, as shown by the observed complete inhibition of cerebral endopeptidase 24.11 after i.v. injection in mice. The prodrug induces strong, dose-dependent antinociceptive responses in mice after i.v., i.p. or s.c. administration, in the hot plate (ED50 = 9 mg/kg) and phenylbenzoquinone-induced writhing (ED50-3.25 mg/kg) tests in mice, which are currently used in analgesics screening. RB101 is also active in the tail-flick and tail-electric stimulation tests in rats. In contrast, under disulfide forms, the above selective aminopeptidase N or endopeptidase 24.11 inhibitors are inactive after i.v. administration and their association 3 times less potent than RB101 alone. In all the tests used, the pain-alleviating effect of RB101 was suppressed by naloxone, but, except for the tail-flick and the motor response to tail-electric stimulation, not by the delta-selective antagonist naltrindole. The preferential involvement of mu opioid receptors in the analgesic effects of endogenous enkephalins, whose extracellular levels are increased by the two RB101-generated inhibitors, is suggested by the similar apparent pA2 values for RB101-naloxone (pA2: 7.53 +/- 0.046) and DAMGO (mu-selective ligand)-naloxone (pA2: 7.38 +/- 0.049).(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: F Noble, J M Soleilhac, E Soroca-Lucas, S Turcaud, M C Fournie-Zaluski, B P Roques
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 261 Issue 1 Pg. 181-90 (Apr 1992) ISSN: 0022-3565 [Print] United States
• PMID: 1560364 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Analgesics
• Disulfides
• Enkephalins
• Enzyme Inhibitors
• Prodrugs
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
• RB 101
• Naloxone
• Phenylalanine
• Aminopeptidases
• Neprilysin

Topics

• Aminopeptidases (antagonists & inhibitors)
• Analgesia
• Analgesics (administration & dosage, pharmacology)
• Animals
• Cell Membrane (drug effects)
• Chromatography, High Pressure Liquid
• Disulfides (pharmacology)
• Drug Interactions
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
• Enkephalins (pharmacology)
• Enzyme Inhibitors (administration & dosage, pharmacology)
• Injections, Intravenous
• Injections, Intraventricular
• Injections, Subcutaneous
• Male
• Mice
• Naloxone (pharmacology)
• Neprilysin (antagonists & inhibitors)
• Phenylalanine (analogs & derivatives, pharmacology)
• Prodrugs (administration & dosage, pharmacology)
• Rats
• Rats, Inbred Strains